Can PKC-Beta Inhibitors Fight Complications?

By C. J. Cahoon and R. Keith Campbell

Although diabetes is known
as a disease of uncontrolled
blood glucose, medical research
has also begun to focus on it as
a blood vessel condition.

Currently, research is under way to study the relation of PKC-beta inhibitors to diabetic retinopathy.

In analyzing exactly how high
blood glucose leads to kidney disease,
neuropathy or retinopathy, researchers
are examining the changes that
uncontrolled glucose levels can cause
in the small blood vessels in the kidneys,
the nerves and the eyes.

Recent and very promising research
is providing some answers
about how prolonged high blood glucose
causes diabetes-related complications,
and it has identified one of
the villains in this process.

Enzymes are proteins made by the
body that bring about chemical reactions.
We now know that the enzyme
PKC-beta (protein kinase C-beta)
acts to increase the formation of new
blood vessels. When such formation
is unwarranted and inappropriate, it
can lead to trouble.

Why Is PKC-Beta So Important to People With Diabetes?
Scientists have found several forms of
this enzyme, all apparently essential
for sustaining life. Some forms are
found more frequently in certain
areas of the body.

PKC-beta is produced in excess
during periods of high blood glucose.
In other words, when there is too
much blood glucose, this enzyme is
turned on “too high.” When PKC-beta
is turned on “too high,” it leads
to the complications related to diabetes—primarily retinopathy, kidney
disease and neuropathy, which are all
related to small blood vessel damage—and possibly to larger blood vessel
damage that can affect the heart.

Exploring the mechanisms that are
involved in turning on PKC-beta
beyond its normal levels is proving to
be an exciting area for new diabetes
research.

How Does High Blood Glucose Lead to Damage?
In addition to high levels of PKC-beta,
a potent hormone growth factor
known as vascular endothelial growth
factor (VEGF) can be released into
the bloodstream as a result of other
complications related to diabetes.
Combined, PKC-beta and VEGF have
the added effect of causing new blood
vessel growth and leakage.

The best example of how this can
create problems is seen in the eye.
When the eye is exposed to prolonged
high blood glucose, it results
in PKC-beta causing new blood vessel
formation and/or leakage. The
leaking blood vessels lead to a condition
known as macular edema. This
causes the retina to swell, leading to
blurred vision and blind spots; if left
untreated, it can even cause retinal
detachment or blindness. Worse, the
newly formed blood vessels can easily
burst, flooding the eye with
blood, which can also lead to total or
partial blindness.

Exciting New Developments
One of the most exciting possibilities
in the efforts to fight diabetes complications
is the development of a PKC-beta
inhibitor.

Eli Lilly and Company has developed
LY333531, a PKC-beta inhibitor
that stops the overgrowth of new
blood vessels and the progression of
the vessel leakage. This new drug
(whose designated generic name is
ruboxistaurin), which may be available
in a couple of years, might eliminate
the negative effect high blood glucose
levels have on the eyes and
kidneys.

Currently, research is under way to
study the relation of PKC-beta inhibitors
to diabetic retinopathy. Theoretically,
a PKC-beta inhibitor has
great potential to benefit patients with
diabetes. Halting the progression of
retinopathy and kidney disease in the
diabetes population could bring in a
new era of treatment.

Roger Corder, professor of experimental
therapeutics at the William
Harvey Research Institute and the
Barts and London School of Medicine,
wrote a commentary in the
September 2002 issue of Clinical
Science discussing the potential future
role of PKC-beta inhibitors in the
treatment of diabetes-related complications.

Corder states that based on animal
studies—primarily with rats—LY333531
inhibits PKC-beta formation. In rat
studies, this compound has normalized
retinal and kidney vascular function,
though not completely to the
level of kidney function found in nondiabetic
rats.

More recent studies also show
improvement of impaired nerve function
in diabetic rats. Corder therefore
speculates that PKC-beta inhibitors
will play a role in the treatment of
diabetes-related microvascular complications
such as eye disease, kidney
disease and nerve damage.

He notes that phase 2 and 3 clinical
trials, involving humans, are currently
being conducted and adds that this
novel drug may also have a role in
treating macrovascular disease involving
the heart and large blood vessels,
although this remains to be proven in
studies.

Tight Control Still the Best Weapon
Despite the potential held out by this
new research, the greatest weapon
people with diabetes have is tight control
of blood glucose. Near-normalization
of blood-glucose levels remains
the primary goal of diabetes
treatment and care.

This article originally appeared in the June 2003 issue of Diabetes Interview and I reproduce it here courtesy of Publisher Scott King.